EP0955297A1 - Un procédé amélioré pour la préparation des statines - Google Patents

Un procédé amélioré pour la préparation des statines Download PDF

Info

Publication number: EP0955297A1
Authority: EP; European Patent Office
Prior art keywords: reaction; lactonization; statins; acid; solvent
Prior art date: 1998-04-22
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Granted

Application number

EP98123252A

Other languages

German (de)

English (en)

Other versions

EP0955297B9 (fr

EP0955297B1 (fr

Inventor

Yatendra Kumar

Rajest Kumar Thaper

S.M. Dileep Kumar

Jag Mohan Khanna

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Ranbaxy Laboratories Ltd

Original Assignee

Ranbaxy Laboratories Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1998-04-22

Filing date

1998-12-07

Publication date

1999-11-10

1998-04-22 Priority claimed from US09/064,285 external-priority patent/US5917058A/en

1998-12-07 Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd

1999-11-10 Publication of EP0955297A1 publication Critical patent/EP0955297A1/fr

2004-04-21 Application granted granted Critical

2004-04-21 Publication of EP0955297B1 publication Critical patent/EP0955297B1/fr

2004-12-15 Publication of EP0955297B9 publication Critical patent/EP0955297B9/fr

2018-12-07 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones

Definitions

Lovastatin and its analogs are potent antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase.
statins which may be referred to,generally as statins, are known to exist in open ring hydroxy acid and also in lactone form.
the lactone form and the hydroxy acid form of these compounds have the following general structural Formulas: wherein Z is hydrogen, a metal cation, such as sodium or potassium, or NH 4 , and R is wherein R 1 is H or CH 3 .
statins The open hydroxy acid form of the statins (Formula II) is the one which is biologically active. However, the statins are generally administered to a patient in the lactone form (Formula I), which is converted to its active metabolite, the hydroxy acid form, in the body.
U.S. patent No. 4,916,239 discloses another process wherein the lactonization reaction is carried out at room temperature by treating the free hydroxy acid ammonium salt of a mevinic acid in a mixture of acetic acid and water, and in the presence of a strong acid catalyst. After the free hydroxy acid-lactone equilibrium is established (reaction has proceeded to 50% conversion), water is gradually added in lots to effect crystallization of the lactone from the reaction medium. This removal of lactone continuously shifts the equilibrium to the lactone side thus leading to reaction completion.
This process suffers from several disadvantages and is also not convenient to operate at a large scale for a variety of reasons, some of which are discussed below
a strong mineral or an organic acid catalyst e.g., formic, phosphoric, trifluoroacetic, sulphuric, hydrochloric, p-toluene sulphonic, methanesulphonic acids, etc.
a strong mineral or an organic acid catalyst e.g., formic, phosphoric, trifluoroacetic, sulphuric, hydrochloric, p-toluene sulphonic, methanesulphonic acids, etc.
the excess acid catalyst which is used needs to be neutralized by adding a strong base before filtration of the product.
the aim of the present invention is to provide an efficient method for lactonization of statins which method avoids the use of strong corrosive acids and drastic heat conditions and gives a lactonized product of high purity and yield.
the present invention provides a novel process for converting the HMG-CoA reductase inhibitors, e.g., the open hydroxy acid forms of lovastatin, simvastatin, and analogs thereof, into their lactone forms, and is convenient to operate on an industrial scale. It allows the lactonizaion reaction to proceed at moderate temperatures without the use of industrially unsafe strong acids.
HMG-CoA reductase inhibitors e.g., the open hydroxy acid forms of lovastatin, simvastatin, and analogs thereof
the process of this invention comprises treating the open hydroxy acid of the statins, preferably in their salt form, most preferably in their ammonium salt form with acetic acid and in the absence of a strong acid catalyst, under inert anhydrous conditions and at ambient to moderate temperatures.
a strong acid is generally regarded as an acid having pK a ⁇ 0).
the lactonization reaction proceeds without the addition of strong acid catalysts (as in the prior art), is clean and fast, thus allowing less chance for impurity formation.
the lactonized product generally having high solubility in acetic acid, is isolated in pure form after completion of reaction by the addition of an anti-solvent which has the ability to crystallize out the lactonized product.
the anti-solvent is selected from water, hexane, heptane, cyclohexane, etc., preferably water, hexane or cyclohexane, most preferably, water.
lactonization is an equilibrium reaction
the reaction by-product ammonia is consumed in situ by the acetic acid, which is present in excess in the reaction medium, to generate ammonium acetate.
the latter being hygroscopic in nature, has a tendency to absorb water, which is also formed as a by-product during the lactonization reaction. There is, therefore, provided a mechanism which allows in situ removal of ammonia and water thereby driving the lactonization reaction to completion.
the rate of lactonization is very high and allows the reaction to be completed in a very short period and the lactone product is obtained in high yields and high purity.
the reaction is carried out at a temperature from ambient temperature to about 55°C, preferably at about 25-45°C, most preferably at about 35-40°C.
the amount of acetic acid is at least about 1 part by volume per part of the starting salt material.
Higher amounts of solvent and generally up to about 20 parts by volume may be used.
the solvent is in the range of about 3 to 7 parts by volume.
the reaction will typically be accomplished within about 3-5 hrs. However, length of time will vary depending on such factors as total volume of solution, temperature of the reaction and the substrate involved.
Major advantages of the present invention as compared to the prior art procedures are cost effectiveness, less cumbersome workup, high yield, increased process productivity, clean and environmentally friendly operations.
the level of impurity profile, especially for the starting acid and the dimer, are greatly reduced as compared to earlier reported processes.
the product which is in the form of a homogenous slurry makes the filtration operations at large scale very easy and workup involves no neutralization step prior to filtration.

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Pyrane Compounds (AREA)
Saccharide Compounds (AREA)
Glass Compositions (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)

EP98123252A 1998-04-22 1998-12-07 Un procédé amélioré pour la préparation des statines Expired - Lifetime EP0955297B9 (fr)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US09/064,285 US5917058A (en)	1997-10-28	1998-04-22	Process of lactonization in the preparation of statins
US64285		1998-04-22

Publications (3)

Publication Number	Publication Date
EP0955297A1 true EP0955297A1 (fr)	1999-11-10
EP0955297B1 EP0955297B1 (fr)	2004-04-21
EP0955297B9 EP0955297B9 (fr)	2004-12-15

Family

ID=22054869

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP98123252A Expired - Lifetime EP0955297B9 (fr)	1998-04-22	1998-12-07	Un procédé amélioré pour la préparation des statines

Country Status (10)

Country	Link
EP (1)	EP0955297B9 (fr)
AT (1)	ATE264849T1 (fr)
DE (1)	DE69823333T2 (fr)
DK (1)	DK0955297T3 (fr)
ES (1)	ES2217485T3 (fr)
HK (1)	HK1023572A1 (fr)
HU (1)	HUP9802936A3 (fr)
PT (1)	PT955297E (fr)
RU (1)	RU2214407C2 (fr)
ZA (1)	ZA9810764B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
WO2002094804A1 (fr) *	2001-05-18	2002-11-28	Aurobindo Pharma Limited	Procede permettant la lactonisation pour la production de simvastatine
EP1288212A1 (fr) *	2001-08-27	2003-03-05	CHEIL JEDANG Corporation	Procédé de lactonisation dans la préparation de statins
US6573385B1 (en)	1999-11-11	2003-06-03	Biocon India Limited	Process for manufacturing simvastatin and novel intermediates thereof
US6573392B1 (en)	1999-11-11	2003-06-03	Biocon India Limited	Process for manufacturing simvastatin and the novel intermediates
US6603022B1 (en)	2002-05-10	2003-08-05	Biocon India Limited	Process for manufacturing Simvastatin and novel intermediates thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4820850A (en) *	1987-07-10	1989-04-11	Merck & Co., Inc.	Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof
US4916239A (en) *	1988-07-19	1990-04-10	Merck & Co., Inc.	Process for the lactonization of mevinic acids and analogs thereof
EP0511867A1 (fr) *	1991-05-01	1992-11-04	Merck & Co. Inc.	Procédé d'obtention de la simvastatine
US5393893A (en) *	1993-11-08	1995-02-28	Apotex, Inc.	Process for producing simvastatin and analogs thereof

1998
- 1998-11-25 ZA ZA9810764A patent/ZA9810764B/xx unknown
- 1998-12-07 AT AT98123252T patent/ATE264849T1/de not_active IP Right Cessation
- 1998-12-07 PT PT98123252T patent/PT955297E/pt unknown
- 1998-12-07 DK DK98123252T patent/DK0955297T3/da active
- 1998-12-07 DE DE69823333T patent/DE69823333T2/de not_active Expired - Fee Related
- 1998-12-07 ES ES98123252T patent/ES2217485T3/es not_active Expired - Lifetime
- 1998-12-07 EP EP98123252A patent/EP0955297B9/fr not_active Expired - Lifetime
- 1998-12-09 RU RU98122366/04A patent/RU2214407C2/ru not_active IP Right Cessation
- 1998-12-16 HU HU9802936A patent/HUP9802936A3/hu unknown
2000
- 2000-05-08 HK HK00102749A patent/HK1023572A1/xx not_active IP Right Cessation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4820850A (en) *	1987-07-10	1989-04-11	Merck & Co., Inc.	Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof
US4916239A (en) *	1988-07-19	1990-04-10	Merck & Co., Inc.	Process for the lactonization of mevinic acids and analogs thereof
EP0511867A1 (fr) *	1991-05-01	1992-11-04	Merck & Co. Inc.	Procédé d'obtention de la simvastatine
US5393893A (en) *	1993-11-08	1995-02-28	Apotex, Inc.	Process for producing simvastatin and analogs thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6573385B1 (en)	1999-11-11	2003-06-03	Biocon India Limited	Process for manufacturing simvastatin and novel intermediates thereof
US6573392B1 (en)	1999-11-11	2003-06-03	Biocon India Limited	Process for manufacturing simvastatin and the novel intermediates
WO2002094804A1 (fr) *	2001-05-18	2002-11-28	Aurobindo Pharma Limited	Procede permettant la lactonisation pour la production de simvastatine
EP1288212A1 (fr) *	2001-08-27	2003-03-05	CHEIL JEDANG Corporation	Procédé de lactonisation dans la préparation de statins
US6603022B1 (en)	2002-05-10	2003-08-05	Biocon India Limited	Process for manufacturing Simvastatin and novel intermediates thereof

Also Published As

Publication number	Publication date
ZA9810764B (en)	1999-08-13
EP0955297B9 (fr)	2004-12-15
HU9802936D0 (en)	1999-02-01
RU2214407C2 (ru)	2003-10-20
EP0955297B1 (fr)	2004-04-21
DE69823333D1 (de)	2004-05-27
DK0955297T3 (da)	2004-08-16
HUP9802936A3 (en)	2000-04-28
HK1023572A1 (en)	2000-09-15
PT955297E (pt)	2004-08-31
ES2217485T3 (es)	2004-11-01
DE69823333T2 (de)	2005-04-07
ATE264849T1 (de)	2004-05-15
HUP9802936A2 (hu)	1999-11-29

Publication	Publication Date	Title
US5917058A (en)	1999-06-29	Process of lactonization in the preparation of statins
KR970011286B1 (ko)	1997-07-09	메빈산 및 이의 동족체의 락톤화 방법 및 이로부터 제조된 락톤
KR100407758B1 (ko)	2003-12-01	스타틴의 제조에 있어서 락톤화 방법
US5939564A (en)	1999-08-17	Process of lactonization in the preparation of statins
EP0955297B1 (fr)	2004-04-21	Un procédé amélioré pour la préparation des statines
US20040068123A1 (en)	2004-04-08	Process for preparing simvastatin
KR100423892B1 (ko)	2004-03-22	스타틴의 제조에 있어서 새로운 락톤화 방법
JP3258144B2 (ja)	2002-02-18	テトラヒドロピラン−４−カルボン酸及びそのエステルの製法
JP2004520444A5 (fr)	2005-02-17
KR100322630B1 (ko)	2002-08-21	심바스타틴및 이의 중간체 화합물을 제조하는 방법
EP1786765B1 (fr)	2009-09-02	Processus ameliore de lactonisation dans la fabrication de statines
NZ552342A (en)	2009-11-27	An improved process for lactonization in the preparation of statins
ZA200303734B (en)	2004-05-14	A lactonization process.

Legal Events

Date	Code	Title	Description
1999-09-24	PUAI	Public reference made under article 153(3) epc to a published international application that has entered the european phase	Free format text: ORIGINAL CODE: 0009012
1999-11-10	AK	Designated contracting states	Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE
1999-11-10	AX	Request for extension of the european patent	Free format text: AL;LT;LV;MK;RO;SI
2000-07-05	17P	Request for examination filed	Effective date: 20000510
2000-07-19	AKX	Designation fees paid	Free format text: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE
2002-07-03	17Q	First examination report despatched	Effective date: 20020523
2003-09-12	GRAP	Despatch of communication of intention to grant a patent	Free format text: ORIGINAL CODE: EPIDOSNIGR1
2003-12-12	GRAS	Grant fee paid	Free format text: ORIGINAL CODE: EPIDOSNIGR3
2004-03-05	GRAA	(expected) grant	Free format text: ORIGINAL CODE: 0009210
2004-04-21	AK	Designated contracting states	Kind code of ref document: B1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE
2004-04-21	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20040421
2004-04-21	REG	Reference to a national code	Ref country code: GB Ref legal event code: FG4D
2004-04-30	BECA	Be: change of holder's address	Owner name: RANBAXY LABORATORIES LTD19 NEHRU PLACE, NEW DELHI Effective date*: 20040421
2004-04-30	REG	Reference to a national code	Ref country code: CH Ref legal event code: EP
2004-05-19	REG	Reference to a national code	Ref country code: IE Ref legal event code: FG4D
2004-05-27	REF	Corresponds to:	Ref document number: 69823333 Country of ref document: DE Date of ref document: 20040527 Kind code of ref document: P
2004-06-30	REG	Reference to a national code	Ref country code: CH Ref legal event code: NV Representative=s name: CRONIN INTELLECTUAL PROPERTY
2004-07-13	REG	Reference to a national code	Ref country code: SE Ref legal event code: TRGR
2004-07-19	REG	Reference to a national code	Ref country code: GR Ref legal event code: EP Ref document number: 20040402156 Country of ref document: GR
2004-07-28	RAP2	Party data changed (patent owner data changed or rights of a patent transferred)	Owner name: RANBAXY LABORATORIES, LTD.
2004-08-16	REG	Reference to a national code	Ref country code: DK Ref legal event code: T3
2004-08-31	REG	Reference to a national code	Ref country code: PT Ref legal event code: TE4A Free format text: RANBAXY LABORATORIES LIMITED IN Effective date: 20040622 Ref country code: PT Ref legal event code: SC4A Free format text: AVAILABILITY OF NATIONAL TRANSLATION Effective date: 20040622
2004-10-01	NLT2	Nl: modifications (of names), taken from the european patent patent bulletin	Owner name: RANBAXY LABORATORIES, LTD.
2004-11-01	REG	Reference to a national code	Ref country code: ES Ref legal event code: FG2A Ref document number: 2217485 Country of ref document: ES Kind code of ref document: T3
2004-12-03	ET	Fr: translation filed
2004-12-04	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: FI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041204
2004-12-07	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041207 Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041207 Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041207
2004-12-08	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041208
2004-12-13	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: AT Payment date: 20041213 Year of fee payment: 7
2004-12-16	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: ES Payment date: 20041216 Year of fee payment: 7
2004-12-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: MC Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041231 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041231 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041231 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041231
2005-01-03	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: DK Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20050103
2005-02-25	PLBE	No opposition filed within time limit	Free format text: ORIGINAL CODE: 0009261
2005-02-25	REG	Reference to a national code	Ref country code: HK Ref legal event code: GR Ref document number: 1023572 Country of ref document: HK
2005-02-25	STAA	Information on the status of an ep patent application or granted ep patent	Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT
2005-04-13	26N	No opposition filed	Effective date: 20050124
2005-06-30	BERE	Be: lapsed	Owner name: RANBAXY LABORATORIES LTD Effective date*: 20041231
2005-07-01	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20050701 Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20050701
2005-07-04	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: GR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20050704
2005-07-25	REG	Reference to a national code	Ref country code: DK Ref legal event code: EBP
2005-07-27	GBPC	Gb: european patent ceased through non-payment of renewal fee	Effective date: 20041207
2005-08-02	EUG	Se: european patent has lapsed
2005-08-15	REG	Reference to a national code	Ref country code: CH Ref legal event code: PL
2005-08-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20050831
2005-09-01	NLV4	Nl: lapsed or anulled due to non-payment of the annual fee	Effective date: 20050701
2005-09-07	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: PT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20050907
2005-09-21	REG	Reference to a national code	Ref country code: IE Ref legal event code: MM4A
2005-10-07	REG	Reference to a national code	Ref country code: FR Ref legal event code: ST
2005-10-31	REG	Reference to a national code	Ref country code: PT Ref legal event code: MM4A Effective date: 20050907
2005-12-07	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20051207 Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20051207
2005-12-09	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20051209
2007-03-16	REG	Reference to a national code	Ref country code: ES Ref legal event code: FD2A Effective date: 20051209
2007-12-31	BERE	Be: lapsed	Owner name: RANBAXY LABORATORIES LTD Effective date*: 20041231
2008-06-30	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: PT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041207

EP0955297A1 - Un procédé amélioré pour la préparation des statines - Google Patents

Info

Links

Classifications

Definitions

Landscapes

Applications Claiming Priority (2)

Publications (3)

Family

ID=22054869

Family Applications (1)

Country Status (10)

Cited By (5)

Citations (4)

Patent Citations (4)

Cited By (5)

Also Published As

Similar Documents

Legal Events